Dai Cheng, Shen Bin, Liu Shenyan, Li Cong, Yang Shuqun, Wang Jie, Zhang Jie, Liu Manqi, Zhu Zhixuan, Shi Wan, Zhang Qi, Chen Zhui, Zhang Nannan
Abbisko Therapeutics Co., Ltd, Shanghai, 201203, China.
J Transl Med. 2025 Aug 12;23(1):900. doi: 10.1186/s12967-025-06920-6.
Osteosarcoma is the most common primary malignant bone tumor affecting children and young adults. Metastatic osteosarcoma has poor prognosis and represents a significant unmet medical need in clinical settings. The CSF-1/CSF-1R signaling pathway is essential for the physiological functions of myeloid lineage cells, including osteoclasts and monocytes/macrophages. The purpose of this study is to investigate the role of CSF-1R in osteosarcoma pathogenesis and the therapeutical potentiality of CSF-1R inhibitor for osteosarcoma patients.
CSF-1, CSF-1R, and IL-34 expression across cancer types were evaluated using public database. Immunohistochemistry (IHC) was utilized to analyze human tissue microarray samples of osteosarcoma. We then investigated the anti-tumor effect and the mechanisms of action of pharmacologic inhibition of CSF-1R activity by pimicotinib (ABSK021), a highly potent and selective small molecule inhibitor of CSF-1R, in osteosarcoma models both in vitro and in vivo.
IHC analysis of human tissue microarray samples revealed a high prevalence of CSF-1R overexpression in osteosarcoma patient samples. ABSK021 effectively inhibited CSF-1R signaling and the proliferation of osteosarcoma cells with high expression of CSF-1R, by inducing cell cycle arrest and apoptosis. In contrast, it had a marginal effect on osteosarcoma cell lines with low CSF-1R expression. In animal studies, ABSK021 demonstrated strong anti-tumor activity in both a syngeneic mouse osteosarcoma model and osteosarcoma patient sample-derived xenograft (PDX) models with CSF-1R overexpression. The analysis of endpoint tumor samples revealed downregulation of CSF-1R signaling and proliferative marker Ki67, along with the increase of apoptotic marker cleaved caspase-3, confirming the on-target effects of ABSK021 in vivo. Furthermore, combining ABSK021 with standard-of-care chemotherapy showed enhanced anti-tumor activity both in vitro and in vivo.
These findings conclusively demonstrated that pharmacological inhibition of CSF-1R activity by ABSK021 resulted in significant anti-tumor effects in preclinical osteosarcoma models with CSF-1R overexpression. The high prevalence of CSF-1R expression observed in osteosarcoma patient samples highlights the potential clinical use of ABSK021, either as a monotherapy or in combination with chemotherapy, as a promising therapeutic strategy for osteosarcoma patients with CSF-1R as a potential predictive biomarker.
骨肉瘤是影响儿童和青年的最常见原发性恶性骨肿瘤。转移性骨肉瘤预后较差，是临床中尚未满足的重大医疗需求。集落刺激因子1（CSF-1）/集落刺激因子1受体（CSF-1R）信号通路对于包括破骨细胞和单核细胞/巨噬细胞在内的髓系细胞的生理功能至关重要。本研究的目的是探讨CSF-1R在骨肉瘤发病机制中的作用以及CSF-1R抑制剂对骨肉瘤患者的治疗潜力。
使用公共数据库评估不同癌症类型中CSF-1、CSF-1R和白细胞介素34（IL-34）的表达。利用免疫组织化学（IHC）分析骨肉瘤的人体组织微阵列样本。然后，我们在体外和体内骨肉瘤模型中研究了CSF-1R的强效选择性小分子抑制剂吡美替尼（ABSK021）对CSF-1R活性进行药理抑制的抗肿瘤作用及其作用机制。
对人体组织微阵列样本的IHC分析显示，骨肉瘤患者样本中CSF-1R过表达的发生率很高。ABSK021通过诱导细胞周期停滞和凋亡，有效抑制了CSF-1R信号传导以及CSF-1R高表达的骨肉瘤细胞的增殖。相比之下，它对CSF-1R表达低的骨肉瘤细胞系影响较小。在动物研究中，ABSK021在同基因小鼠骨肉瘤模型和CSF-1R过表达的骨肉瘤患者样本来源的异种移植（PDX）模型中均表现出强大的抗肿瘤活性。对终点肿瘤样本的分析显示CSF-1R信号传导和增殖标志物Ki67下调，同时凋亡标志物裂解的半胱天冬酶-3增加，证实了ABSK021在体内的靶向作用。此外，将ABSK021与标准护理化疗联合使用在体外和体内均显示出增强的抗肿瘤活性。
这些发现确凿地证明，ABSK021对CSF-1R活性的药理抑制在CSF-1R过表达的临床前骨肉瘤模型中产生了显著的抗肿瘤作用。在骨肉瘤患者样本中观察到的CSF-1R表达的高发生率突出了ABSK021作为单一疗法或与化疗联合使用作为具有CSF-1R作为潜在预测生物标志物的骨肉瘤患者的有前景治疗策略的潜在临床应用。
